Influence of Exceptional Patient Characteristics on Everolimus Exposure

Breast Neoplasms Clinical Trial

— INPRES  

Official title:

Influence of Exceptional Patient Characteristics on Everolimus Exposure

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01948960
• Other study ID #: UMCNONCO201301
• Status: Completed
• Phase: Phase 4
• Start date: August 2013
• Est. completion date: January 15, 2018

Study information

• Verified date: October 2017
• Source: Radboud University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

A study to determine whether everolimus pharmacokinetics in elderly and obese patients is different compared to control patients.

Furthermore the investigators will investigate the relation between metabolic response assessed with [18F] Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET) and everolimus exposure and clinical benefit.

The investigators will explore whether dose escalation in patients who are hypothetically underexposed will result in an increase in metabolic response.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 56
• Est. completion date: January 15, 2018
• Est. primary completion date: January 15, 2018
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Adult women (= 18 years of age) with metastatic or locally advanced breast cancer not amenable to curative treatment by surgery or radiotherapy.

• Histological or cytological confirmation of estrogen-receptor positive (ER+) breast cancer

• Postmenopausal women

• Radiological or clinical evidence of recurrence or progression on last systemic therapy prior to enrollment.

• Progression following a non-steroidal aromatase inhibitor

• Falling into one of the following categories

• elderly patients (age = 70 years and BMI < 30 kg/m2); or

• obese patients (BMI = 30 kg/m2 and age < 70 years); or

• control patients (BMI < 30 kg/m2 and age < 70 years);

• Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) = 5 x ULN

• Adequate renal function: calculated creatinine clearance, as estimated by GFR using the MDRD formula, is = 30ml/min/1.73m2

• Performance status ECOG 0 - 2 (Karnofsky index: 60 - 100)

• Patient is willing and able to sign the Informed Consent Form prior to screening evaluations

Exclusion Criteria:

• Patients aged = 70 years AND BMI = 30 kg/m2

• HER2-overexpressing patients by local laboratory testing (IHC 3+ staining or in situ hybridization positive).

• Previous treatment with exemestane or mTOR inhibitors. Except for the treatment with exemestane in the adjuvant setting.

• Known hypersensitivity to mTOR inhibitors, e.g. sirolimus (rapamycin).

• Patients with a known history of HIV seropositivity.

• Any severe and / or uncontrolled medical conditions such as:

• Unstable angina pectoris, serious uncontrolled cardiac arrhythmia

• Patients with severe hepatic impairment (Child-Pugh A/B/C)

• Uncontrolled diabetes mellitus

• Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of study drugs (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome)

• Patients who test positive for hepatitis B or C

• Patients being treated with drugs recognized as being strong inhibitors or inducers of the isoenzyme CYP3A within the last 5 days prior to enrollment

• History of non-compliance to medical regimens

• Patients unwilling to or unable to comply with the protocol

Related Conditions & MeSH terms

• Breast Neoplasms

Intervention

Drug:
• everolimus dose escalation
patients with an AUC below mean will have dose escalation of everolimus based on their AUC

Locations

Country	Name	City	State
Netherlands	Maasziekenhuis Pantein	Boxmeer
Netherlands	Spaarne Gasthuis	Hoofddorp
Netherlands	Maastricht University Medical Center	Maastricht
Netherlands	St. Antonius Ziekenhuis	Nieuwegein
Netherlands	Radboud university medical center	Nijmegen
Netherlands	Bernhoven Ziekenhuis	Uden
Netherlands	Isala Klinieken	Zwolle

Sponsors (2)

Lead Sponsor	Collaborator
Radboud University	Novartis

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	everolimus AUC	The primary aim is to show a difference in everolimus exposure (AUC0-24hr) of at least 25% in elderly patients (=70 years) and obese patients (BMI = 30 kg/m2) compared to the control group (= 70 years; BMI = 30 kg/m2), after reaching steady state everolimus pharmacokinetics (day 14, but at least after 7 days of everolimus therapy).	day 14 after start treatment
Secondary	correlation between early metabolic response and PFS	To explore and calculate the predictive value of early metabolic response assessment with clinical benefit (PFS defined as disease progression according to RECIST version 1.1 or death, whichever occurs first) as primary outcome measure.; Metabolic response is defined as fractional change (?SUV and ?TLG), comparing the third en second scan with the baseline scan.	within 90 days after start of treatment
Secondary	correlation between early metabolic response and AUC	To quantify the correlation between early metabolic response and everolimus exposure (AUC0-24hr) on steady-state pharmacokinetics.; Metabolic response is defined as fractional change (?SUV and ?TLG), comparing the third en second scan with the baseline scan.	15 days after start of treatment
Secondary	effect dose escalation on metabolic respons	To explore, quantify and describe whether dose escalation in patients who are hypothetically underexposed will result in an increase in metabolic response.; Metabolic response is defined as fractional change (?SUV and ?TLG), comparing the third en second scan with the baseline scan.	within 36 days after start of treatment
Secondary	correlation between AUC and frequency of adverse event	To explore, quantify and describe the correlation between everolimus exposure and the frequency of adverse events as graded with CTCAE v4.0.	4 months after start of treatment

External Links

•   Everolimus Exposure and Early Metabolic Response as Predictors of Treatment Outcomes in Breast Cancer Patients Treated with Everolimus and Exemestane